Co-Editor-in-Chief of Stem Cell Research & Therapy Rocky Tuan discusses the road to developing 3D microphysiological systems for testing drug toxicity and efficacy, following a supplement in Stem Cell Research & Therapy from leading researchers involved in the US National Institutes of Health Microphysiological Systems program.
Experimental model systems have long served an important role in biomedical research – to gain fundamental insights into biological mechanisms and pathways, to test the effects of putative therapies, and to detect potential toxicities of chemicals and unknown agents.
Organismal models constituted early attempts, while advances in tissue and cell culture systems, first developed in early 20th century, have ushered in more defined and analytical laboratory-based approaches that permit more in-depth studies of cellular and molecular events. These systems generally utilize culture vessels consisting of confined, two-dimensional ceramic or polymeric substrates for cell growth, which provide convenience in handling, imaging, and monitoring. Although these systems have yielded a tremendous wealth of information and knowledge on biological processes, they are fundamentally deficient in modeling physiological processes in whole organisms, because of the lack of three-dimensional tissue architecture and multi-organ tissue interactions. In contrast, animal models such as rats and rabbits, that are commonly used in drug toxicity or efficacy screens, are not complete human physiological mimics, and thus often fail to faithfully reproduce complex biological interactions and pathways or predict potential harmful or beneficial effects. A paradigm shift has thus been emerging in recent years to develop more robust, physiologically relevant model systems.
Recognizing this need, the United States National Institutes of Health (NIH), in partnership with the US Defense Advanced Research Projects Agency (DARPA) and the US Food and Drug Agency (FDA), initiated a Microphysiological Systems (MPS) Program in 2012, to accelerate the development of human MPS that will improve the reliability to identify human drug toxicities and predict the potential efficacy of a drug in a human population prior to use of the drug in late-stage clinical studies. The goal of the NIH MPS Program is to create and integrate MPS that utilize human primary or stem cell sources, which are sustainable over a four week period and functionally represent the ten major organ systems: circulatory, respiratory, integumentary, reproductive, endocrine, gastrointestinal, nervous, urinary, musculoskeletal, and immune.
In the 2013 Supplement of Stem Cell Research and Therapy, titled Stem Cells on Bioengineered Microphysiological Platforms for Disease Modeling and Drug Testing, the 19 investigators currently involved in the NIH MPS contributed mini-review articles describing advances in their respective systems, providing an exciting overview of the potential of the MPS approach in modeling biological systems and activities. This consortium of research activities represents interests from 15 Institutes/Centers of the NIH. The topics covered include experimental models for neurovascular systems, kidney, liver, myocardiac tissues, metastatic processes, osteochondral tissue, muscle, lung, intestine, brain, and skin. The cell sources employed range from adult mesenchymal stem cells, various tissue progenitor cells, embryonic stem cells, and induced pluripotent stem cells, utilizing state-of-the-art microfluidic, mechanoactive, and imaging-compatible microbioreactors.
This funding initiative represents an exciting development in the biomedical research landscape, as it represents the first time that a consortial approach, with substantive, targeted federal funding support, is taken to synergize multi-disciplinary and multi-system platforms. The objective, as stated in the MPS Program is to achieve an interactive, ‘plug-and-play’, multi-tissue platform that faithfully represents human physiology. Three-dimensional ‘tissue-on-a-chip’ (perhaps best coined as ‘Homo chipiens’) promises to present a new and rewarding experimental paradigm to the understanding of human biology and disease pathogenesis, and development of effective disease modifying therapies.
The complete list of supplement articles: